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Concept: Gluten sensitivity

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Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.

Concepts: Epidemiology, Disease, Wheat, Irritable bowel syndrome, Coeliac disease, Gluten, Wheat allergy, Gluten sensitivity

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Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts' recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally.

Concepts: Medical terms, Wheat, Coeliac disease, Gluten, Gluten-free diet, Dermatitis herpetiformis, Wheat allergy, Gluten sensitivity

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Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.

Concepts: Immune system, Wheat, Constipation, Irritable bowel syndrome, Flatulence, Coeliac disease, Wheat allergy, Gluten sensitivity

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Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related syndrome defined as non-celiac gluten sensitivity. Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%. From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced. Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten challenge is currently the diagnostic method with the highest accuracy. Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a condition that has global acceptance but has only a few certainties and many unresolved issues.Cellular & Molecular Immunology advance online publication, 12 August 2013; doi:10.1038/cmi.2013.28.

Concepts: Immune system, Nutrition, Digestive system, Wheat, Coeliac disease, Gluten, Wheat allergy, Gluten sensitivity

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Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra-intestinal symptoms that are related to the ingestion of gluten in subjects who are not affected by either celiac disease (CD) or wheat allergy (WA). In this multicenter study, we aim for the first time to evaluate the prevalence of NCGS in pediatric subjects with chronic functional gastrointestinal symptoms associated with gluten ingestion using a double-blind placebo-controlled (DBPC) gluten challenge with crossover.

Concepts: Medicine, Disease, Wheat, Coeliac disease, Gluten, Gluten-free diet, Wheat allergy, Gluten sensitivity

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It has been found that celiac disease (CD) and non-celiac gluten sensitivity (NCGS) have a high prevalence in fibromyalgia (FM) patients. NCGS is a relatively new entity characterized by gastrointestinal and extra-intestinal manifestations in the absence of CD or wheat allergy. It is different from CD because anti-transglutaminase (anti-tTG) or endomysial antibodies (IgA-EmA) are lacking and the intestinal mucosa is normal or with mild abnormalities as increased intraepithelial lymphocytes in the absence of villous atrophy.

Concepts: Immune system, Antibody, Wheat, Coeliac disease, Gluten, Gluten-free diet, Wheat allergy, Gluten sensitivity

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Knowing whether or not a food contains gluten is vital for the growing number of individuals with celiac disease and non-celiac gluten sensitivity. Questions have recently been raised about whether beef from conventionally-raised, grain-finished cattle may contain gluten. To date, basic principles of ruminant digestion have been cited in support of the prevailing expert opinion that beef is inherently gluten-free. For this study, gluten analysis was conducted in beef samples collected using a rigorous nationally representative sampling protocol to determine whether gluten was present. The findings of our research uphold the understanding of the principles of gluten digestion in beef cattle and corroborate recommendations that recognize beef as a naturally gluten-free food.

Concepts: Wheat, Cattle, Coeliac disease, Gluten, Gluten-free diet, Dermatitis herpetiformis, Wheat allergy, Gluten sensitivity

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A new syndrome responding to gluten-free diet and defined non-celiac gluten sensitivity entered the spectrum of gluten-related disorders, together with celiac disease and wheat allergy. However, its definition, prevalence, diagnosis, pathogenesis, treatment, and follow up are still controversial. The purpose of the review is to summarize the evidence and problems emerging from the current literature.

Concepts: Wheat, Coeliac disease, Gluten, Gluten-free diet, Dermatitis herpetiformis, Rice, Wheat allergy, Gluten sensitivity

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Although no biomarker has been identified to date, previous studies have reported that about 50% of patients with suspected Non Celiac Gluten Sensitivity (NCGS) had positive first generation anti- gliadin antibodies (AGAs), expecially of the IgG class. These antibodies are not specific for NCGS, being also found in CD (80-90%), autoimmune liver disorders (21.5%), connective tissue disease (9%) and IBS (20%), as well as in healthy controls (2-8%), but their finding in patients with a clinical phenotype consistent with NCGS has been regarded as an element supporting this diagnosis. Even if the correlation between AGA IgG and NCGS condition turned out to be statistically significant in most studies, AGA IgG doesn’t seem to be an adequately strong marker for its lacking diagnostic accuracy. However it can partly help the NCGS diagnosis, integrated in the overall management of the patient. Therefore, in the presence of clinical symptoms that suggest NCGS, IgG AGA positivity, together with negative anti-tTG, EMA, and anti deamidated gliadin peptides (DGP) antibodies, NCGS diagnosis might be suspected. Future researches are necessary to identify reliable biomarkers for NGCS diagnosis and to better define clinically and serologically NCGS patients.

Concepts: Immune system, Blood, Coeliac disease, Gliadin, Anti-gliadin antibodies, Triticeae glutens, Gluten sensitivity, Gluten-sensitive idiopathic neuropathies

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Non-celiac gluten sensitivity (NCGS), sometimes known as non-celiac wheat sensitivity (NCWS), has recently received much attention, both scientific as well as from the alternative medical community. Over the past 5 years, there are over 200 publications on NCGS indexed on PubMed database, the gluten-free market has been growing bigger, and it is clear that the number of consumers who are on a gluten-free diet (GFD) possibly because of a suspicion for NCGS appears to grow even faster. Nevertheless, despite these three rising events, many questions about NCGS remain unresolved. It is likely that NCGS represents a heterogeneous group of disorders linked by a common response to a GFD. It is still not fully understood how gluten, and likely other wheat proteins and components, could activate and drive the pathophysiology of NCGS. As a result, there are still no clear biomarkers, no robust clinical diagnostic criteria, nor a conclusive definition for NCGS. This heterogeneity can be approached by reducing the variables, in particular those of human behaviour and placebo effect, by studying animal models to address specific biological effects of wheat and/or gluten-related proteins. Herein we review the animal models and their potential to be used to advance our understanding of these disorders and potentially address their prevention and treatment.

Concepts: Wheat, Coeliac disease, Gluten, Gluten-free diet, Rice, Wheat allergy, Wheat gluten, Gluten sensitivity